Project Summary/ Abstract The research scope proposed in this administrative supplement, in response to the funding opportunity PA-18-591 (Administrative Supplements to Existing NIH Grants), will leverage the resources and experience developed in our NIH/NCCAM-funded parent P50 Center Grant for advancing Research on Botanical and Other Natural Products (CARBON). To date, this parent grant has provided critical new insights on both the brain and plasma bioavailability of dietary polyphenols, and has initiated an understanding of the biomolecular mechanisms through which dietary polyphenol metabolites provide resilience against multiple neuropathogenic processes, in particular neuroinflammation. Using the extensive resources and in-depth experience accumulated from our P50 Center Grant, with a specific focus on the technical support from our CORE facilities, the proposed studies in this administrative supplement will investigate if the pharmacological application of brain-bioavailable polyphenol metabolites that we have identified to possess anti- inflammatory activity can preserve the integrity and function of the blood brain barrier (BBB), towards the development of a novel therapeutic against Alzheimer's disease (AD). The degeneration of the BBB is a notably neuropathological feature in neurodegenerative disorders, including AD. Likewise, the upregulation of inflammatory mediators and ensuing chronic neuroinflammation apparent in AD patients decreases the structural integrity of the BBB linking to two neuropathologies. However, to date, a direct mechanistic link between neuroinflammation and BBB integrity in the context of AD has not been elucidated and we believe that approaches using bioavailable polyphenols that suppress neuroinflammatory pathways represent a valuable approach towards preventing causative neuropathologies in AD involving BBB integrity. Of particular interest are the effects of IL-1? overexpression in the brain as IL-1? plays a central role in the progression of neuropathologies observed in AD. Particularly, research has demonstrated that IL-1? directly interferes with the expression of vascular endothelial tight junction proteins by releasing vascular endothelial growth-factor (VEGF)-A, which upon interaction with the VEFG-A receptor, leads to downstream iNOS-mediated down-regulation of junction proteins, which critically support the structural integrity of the BBB and maintain its homeostatic functions. The objective of our research is to, for the first time, comprehensively characterize, through innovative in vitro and in vivo paradigms, a unique panel of 16 brain-bioavailable polyphenol metabolites identified through our P50 parent grant for their anti-inflammatory capabilities and their capacity to buffer against BBB dysregulation. Overall, these studies will provide the mechanistic basis for developing novel strategies using bioactive, brain-bioavailable polyphenol metabolites to promote resilience against AD and other neurological disorders by protecting BBB functional integrity during pro-inflammatory insults.